Integrating safety, security, sustainability, and social responsibility principles into the U.S. bioeconomy

ABSTRACT Bioindustrial manufacturing is undergoing rapid expansion and investment and is seen as integral to nations’ economic progress. Ensuring that bioindustrial manufacturing benefits society as the field expands is of critical, urgent importance. To better understand the industry’s ethical trajectory and to shape policy, we explored the views of biotechnology leaders on four aspects of ethical and social responsibility—safety, security, social responsibility, and sustainability—what we have termed “4S principles.” We identified policy actions governments and other stakeholders may take to maximize societal benefits in industrial biotechnology. IMPORTANCE We analyzed biotech leaders’ views on safety, security, social responsibility, and sustainability to recommend policies to maximize benefits and economic growth.


MATERIALS AND METHODS
The Johns Hopkins University Bloomberg School of Public Health Institutional Review Board determined that this study did not constitute human-subjects research (IRB00023291).

Interviews
From April 2023 to June 2023, the researchers conducted a series of semi-structured, virtual interviews with 31 industry leaders, representing a variety of perspectives from the BioMADE memberships.These leaders included individuals associated with academic institutions, as well as CEOs, founders, CSOs, and CTOs of biomanufacturing companies.BioMADE's membership spans a mix of U.S.-based and international organizations.Reflecting this composition, the majority of the interviewees were representatives of U.S.-based organizations or companies, with a few industry leaders hailing from international companies.The researchers developed an interview guide based on results of an informal conversation with BioMADE leaders, as well as the researcher's personal experience and expertise related to biosafety and biosecurity.While the interview guide included core topics, interviewees were allowed to direct the conversation based on their individual experiences and priorities.All interviews were conducted on a not-for-attribu tion basis to promote candor and transparency.During each interview, a member of the research team took notes and audio was recorded and transcribed-with interviewees' consent-to supplement interview notes.

Analysis
The researchers employed a qualitative approach to analyze interview content, systematically and rigorously documenting the landscape of perceptions associated with BioMADE's 4S principles.Qualitative coding of interview notes was done using NVivo qualitative coding software and priority themes were identified and coded.The initial thematic coding framework was solely based on BioMADE's 4S principles.The research ers added themes as they emerged during the interviews.The final coding framework

Principle Definition
Safety Practices, controls, and measures taken to protect people and the environment from harm from biomanufacturing development processes and/or physical product or byproducts.Includes safety of the workplace, consumers, and the general public.

Security
Measures taken across the biotechnology and biomanufacturing sectors, including food and agriculture, materials, and energy, to manage potential threats and loss due to theft, misuse, diversion, unauthorized possession of property (including intellectual property [IP]) or intentional release of biological risk and/or technology.

Sustainability
Measures taken to maintain or improve the long-term viability of the environment and economy due to advancing biomanufacturing processes.
These would include consideration of the impacts of products and processes on the environment, supply chain, as well as local public/consumer acceptance and practices.

Social responsibility
A principle that acknowledges the impacts of biomanufacturing on stakeholders with respect to associated benefits, risks, and consequences throughout the value chain.This implies taking actions that optimize positive social outcomes through adherence to ethical standards, including seeking ways to make products and processes that improve societal welfare.Special attention to this commitment includes equitable distribution of benefits and risks and a responsiveness to society's needs and values.
a See reference 3.
included the following: sustainability, safety, security, social responsibility, education, public risk perception, competition, regulatory space, and workforce.Using NVivo12 Pro and Microsoft Excel, semi-quantitative metrics were generated for all codes in the framework to measure the frequency with which they were discussed.These metrics included the number of coding references (individual chunks of coded text) corresponding to each code.Some references were co-coded.These descriptive metrics were also used to identify themes discussed more often or more in-depth, which could signal differences in how stakeholders prioritize certain topics.The research team also conducted a thorough qualitative analysis of the coded references, undertaking a detailed review of the coded text corresponding to highlighted codes, enabling the researchers to identify important comments and recommendations, both those that were prevalent across numerous interviews and those that were not.

RESULTS
While the study was not designed to yield quantitative results, the findings reflect the relative frequency with which interviewees discussed topics, expressed viewpoints, or provided recommendations (e.g., "some" or "many" interviewees).

Results overview
Researchers invited 62 industry leaders to participate in this study, of which 31 were interviewed (Table 2).Recruited participants came from a diverse range of academic and industry backgrounds.The majority are BioMADE members, but additional participants were identified through snowball sampling.
The research team performed thematic coding on transcripts, resulting in 580 total coding references.The number of coded references for each of the 4S principles was similar, which was a predictable result as interviews were conducted in such a way as to give participants an equal opportunity to discuss these four principles and all were directly asked about them.Interestingly, additional themes emerged during the interviewing process and the research teams added the following codes: education, public risk perception, competition, regulatory space, and workforce).Of note, the researchers found that many of the references coded to the "security" principle originate from a handful of interviews.

Participants' 4S perceptions
Participants discussed their understanding of each 4S concept.Most industry leaders exhibited a homogeneous understanding of safety, sustainability, and social responsibil ity, there was a diverse understanding of security.Most stakeholders interpreted security concerns as revolving around IP, economic security, supply chain resilience, export control, and cybersecurity.Only a few interviewees expressed concerns about biosecur ity, such as risks like AI-enabled creation of harmful products, toxins, or pathogens (see Table 3).The diversity in definitions of security underscores the complexity of this issue, indicating a need for further research to capture a wider array of understandings and approaches to security among a wider sample of industry leaders.

Barriers and recommendations
Participants identified barriers to the integration of the 4S principles into the industry and outlined potential policy recommendations to address them (see Table 3).

Safety
Many industry leaders highlighted the need for standardized metrics and evaluation methods to integrate safety principles effectively (e.g., biocontainment measures or monitoring and recording of personal or environmental exposure incidents), emphasiz ing the importance of clear definitions and measurement techniques to assess safety compliance.One interviewee commented that "because biotech is so fragmented, safety and security can mean different things to different people, and the significance of it can be different."Other leaders noted the complexity of risk assessments for emerging products, such as de novo proteins and systems.They urged increased investment in researching the safety and security implications of these technologies and the creation of updated risk models with supporting data sets.

Security-biosecurity
Only a few interviewees were interested in biosecurity, defined as measures and practices employed to protect against the misuse of biological substances and technologies.They recommended the USG educate industry members about biosecurity, develop both educational and practical biosecurity tools, and encourage or mandate adherence to security best practices (e.g., screening DNA synthesis orders) through financial incentives or legislation.Some were concerned about the inefficiency of current gene or protein synthesis screening tools, as they may not be effective against sequences designed by AI.These AI-generated sequences refer to genetic or protein patterns that have been conceived by computer algorithms rather than derived from existing natural organisms, potentially posing a challenge for existing screening tools, which are typically optimized to recognize and synthesize genetic materials that are found in nature.Some participants observed that understanding and assessing the interactions among different biological functions within a single cellular system is of crucial importance to understanding potential risks, one noted "what do these biological systems do when put together?And could the outcome be weaponizable?"They emphasized, however, that there is a critical gap in expertise and tools for such assessment and prediction, which heightens biosecurity concerns, including predicting unintended consequences of such interactions and identifying potential dual-use research of concern (DURC).They urged the USG to invest in research for the safety and security of these technologies, develop updated models to predict biological functions for de novo biological products, and consider strengthening the role of National Laboratories to address these challenges, one stated "historically, the government had a responsibility to understand the safety and security implications of emerging technologies.I just don't see that kind of like large scale investment going into the National Lab architecture."

Security-IP and industrial security
Most expressed concerns about IP security, calling for increased investments in genetically built-in protections, where organisms are designed with genetic safeguards that render them nonviable or dysfunctional if used without permission, much like a biological form of piracy prevention.Those technologies would address IP concerns with exports to foreign countries as well as bioterrorism concerns.Other industry leaders noted that as the economy moves toward more bio-based products, biomanufacturing facilities have the potential to become targets for IP theft; the USG should collaborate with companies to identify vulnerabilities to physical and cyberattacks and strengthen security across all production stages.

Security-national and economic security
A handful of industry leaders recommended the USG explore new export control policies and clarify International Traffic in Arms Regulations (ITAR) and other foreign staff requirements for biotech and biomanufacturing; one stated, "we have multiple foreign nationals working on our project, and we're doing our best to not share details beyond what they need to know.[the USG funder] never asked us to think about how we're going to come up with checkpoints.I don't really want more bureaucratic paperwork, but at the same time, it would be useful for them to start thinking about these poten tial concerns."Some advocated for policy research to understand the economic and geopolitical vulnerabilities associated with bio-transition, including data infrastructures and supply chain visibility.They noted that such analysis is vital as it mirrors the strategic importance of managing critical resources like oil and gas.By mapping the sources of capabilities, infrastructure, and materials (e.g., feedstocks), as well as assessing related geopolitical risks, we can develop robust strategies to ensure sustainable, secure, resilient, and equitable access to these key biological resources, mirroring strategies used in traditional energy sectors.

Sustainability
Bio-manufactured products are often associated with reductions in emissions, land use, and water use, but, most industry stakeholders emphasized that absent standardized reporting approaches and tools, generating comparable data is challenging, making it difficult for stakeholders to accurately assess and compare sustainability performance across different organizations or sectors.One participant stated, "I think a lot of people in this space are trying to do better with how they do their sustainability analyses, but it's a challenge as it's not standardized."Consequently, many suggested that the USG should play an active role in developing and standardizing sustainability met rics and benchmarks, particularly for carbon emission reporting and life cycle assess ments, "we need entities like BioMADE, and other public entities, to start supporting a more holistic reviewed approach to measuring sustainability."There was widespread agreement that standardized metrics are essential for consistent, transparent, and credible sustainability assessments, and would empower industry stakeholders to make more informed decisions, support effective policy development, and facilitate market access.Many stakeholders noted the dominance of carbon-based products due to historical investments and incentives, which makes it difficult for bio-based products to compete, as stated by one stakeholder "the fossil fuel incumbent has enjoyed a very substantial policy support system for a very long time."Some recommended that the USG refocus investments on large-scale infrastructure projects to help the transition toward a bio-based economy.USG-sponsored manufacturing hubs could help companies pilot products through subsidization, accelerating product development and bridging the so-called "valley of death" where emerging pilot technologies often struggle to transition to large-scale production.Others thought market or other creative financial incentives (e.g., loan guarantees for the construction of facilities or governmentset industry standards) would promote market creation and drive further investments in the industry.

Social responsibility
All industry stakeholders agreed that the bioeconomy has tremendous potential for equitable job creation across the country, including in disadvantaged or underrepresen ted communities, "biomanufacturing has the potential to create millions of high-paying jobs."Many recommended the USG continue boosting domestic manufacturing jobs, albeit with a larger focus on bio-based manufacturing and equitable access to profes sional opportunities in this industry.Most highlighted that for biomanufacturing to deliver on its social responsibility promises, broader investments in science, technology, engineering, and mathematics (STEM) education are needed beyond the traditional graduate and postgraduate programs, including at the K1-12 levels, trade schools, and community colleges.Others suggested government should play a larger role in addressing diversity issues by co-funding student industry internships making these opportunities more visible and accessible across diverse populations.A handful of participants also called for more active and hands-on engagement with communities and local associations to better understand the impact of new technologies and new manufacturing hubs on their environment, lifestyle, and livelihoods.

Cross-cutting issues
Industry leaders emphasized that if the United States is to be a global leader of the ethical standards and norms within bioindustrial manufacturing, it needs to be a global leader in bioindustrial manufacturing as a field.Thus, it must address challenges impeding U.S. competitiveness in this sector.They highlighted specific cross-cutting areas of interest fundamental to the success and advancement of the biomanufacturing industry and for the successful integration of the 4S Principles.

Regulatory uncertainty
Most interviewees regarded the lack of a unified national regulatory framework for bioindustrial products as a significant barrier to establishing 4S standards across the industry-one stated "safety regulations are completely inconsistent, so everybody gets stalled out" and another "there's really terrible safety regulation uniformity on engi neered organisms in the US." State-by-state approaches, for example in the regulations of genetically engineered crops, and other regulatory disparities among various agencies further complicate matters, affecting public clarity, trust, and the ability of smaller companies and startups to innovate, compete, and expand nationally.Many suggested streamlining the regulatory processes would help bioindustries compete fairly against fossil fuel-based technologies, which have historically enjoyed substantial policy and financial support, "we go through the same regulatory processes as our fossil counter parts.The reality is, we need a separate regulatory system for non-fossil building blocks and ultimately products.We are in the same queue as the products that the [Biden] Administration, and society as a whole, is looking to replace or make more sustainable.We can't have the impact on safety, security, social responsibility, and sustainability if we're all moving in the same pipeline." Some called for a separate, expedited regu latory pathway, based on robust risk assessments so that sustainable products could more easily enter markets.Some technologies do not have a clear pathway at all, including organisms for remediation, which contributes to delays and bottlenecks in these technologies becoming available.Increased resources and expertise within U.S. regulatory agencies were recommended to expedite reforms to facilitate competitive ness.

Education and workforce development
A robust biomanufacturing workforce is needed for the success of the industry; participants cited skilled staff shortages, talent retention issues, and workforce preferen ces as factors exacerbating a critical workforce deficit.Others noted that silos between academia, government, and the private sector hinder knowledge exchange, creating a skills gap and that the absence of standardized national guidelines leads to incon sistency in educational programs.There was widespread agreement that specialized scientific knowledge from advanced education programs is no longer a necessity in the industry and that bachelor's and associate degrees, as well as certificates, could adequately train most workers, and that these training and hiring trends must acceler ate.One participant astutely stated, "the next set of true blue-collar jobs could be enabled by biology." Interviewees suggested government actions to foster a skilled and sustainable biomanufacturing workforce, including implementing workforce develop ment incentives, increasing government funding in K1-12 STEM education, and revising curricula to align more closely with industry demand.To expand access to training, many called for funding community college biomanufacturing programs and provided grants for student internships that help create equal opportunities for practical experience and potential future employment in the biomanufacturing sector.One stakeholder said "general workforce development incentives would be great.This is something that obviously the Inflation Reduction Act and the executive order on biomanufacturing have really focused on.But we need to make sure that this is a career path that is attractive to people coming out of, whether it's high school, or even higher education, and show ing the possible career development."Other leaders noted that targeted immigration reforms and family-friendly policies, like parental leave, attract skilled workers, enrich the talent pool, and demonstrate commitment to a more inclusive workforce.

Public perception
Several identified public perceptions of bio manufactured products as a key risk factor for the overall success and flourishing of the industry, with one participant stating "we could have the safest technology around.But if the community doesn't get it, it's not worth anything."They recommended the USG take strategic actions to avoid public misperceptions of the technology through lessons learned from genetically modified organisms (GMO).Communications could highlight the societal benefits of bio-based technologies, especially regarding climate change and the economy.Some recommen ded a communication strategy focused on products with widely accepted benefits, that replace products that rely on animal or petrochemical inputs.Many noted that engaging directly with communities is essential to build public trust and support biotechnologies and products.

Competition
Many stakeholders highlighted the importance of making the industry more competitive as a critical step toward integrating the 4S Principles but cited several barriers hampering these efforts.The influence of powerful competitor lobbies, including petrochemicals, was named by most participants as a critical barrier to the industry's advancement, with one stakeholder stating "1 billion dollars funding…that's a blip compared to the monolith of petrochemicals."Others cited the fragmented regulatory landscape as a major hurdle for innovation and competitiveness, while some highlighted the high cost of building biomanufacturing facilities, coupled with limited competition in raw material supply, as major challenges for smaller companies and start-ups.Some interviewees suggested that the USG expand loan guarantee programs and leverage National Labs as pre-competitive hubs, to facilitate scaling and pilot studies without extensive private investment.The majority also agreed that it was critical for policymakers to involve the science, technology, and engineering communities in policy development to better support the biomanufacturing industry's growth competitiveness.

DISCUSSION
In response to the potential global technology race, global powers such as China, the UK, and the EU are rapidly expanding their biomanufacturing capacity and workforce.China, in particular, is narrowing the gap with the U.S. through aggressive R&D investments, targeted government directives under their "Made in China 2025" plan, and a strong focus on STEM talent attraction and retention (4,5).President Biden's Executive Order (EO) 14081, issued on 12 September 2022, initiated the "National Biotechnology and Biomanufacturing Initiative, " which outlines a whole-of-government approach to propel biotechnology and biomanufacturing towards innovative solutions in various critical areas, such as health, climate change, energy, food security, agriculture, supply chain resilience, and national and economic security.Meeting the EO's ambitious targets would not only establish a solid basis of U.S. leadership and competitiveness in biobased manufacturing but would also position it to lead the shaping of international ethical standards and norms (6).
The interviews conducted in this study yielded valuable recommendations for the integration of the 4S principles into the industry at large.However, a key takeaway emphasizes that for the United States to truly become a standards-setter rather than a standard-taker, it must first secure its position as a competitive leader.The study's recommendations share common ground with the insights from the National Academies of Sciences, Engineering and Medicines (NASEM)'s commission on Safeguarding the Bioeconomy, particularly in the emphasis on evaluating the environmental and health benefits tied to the bioeconomy.NASEM's report also acknowledged the importance of strengthening intellectual property (IP) and cybersecurity measures to protect and propel the bioeconomy forward (1).
Industry stakeholders interviewed in this study have also emphasized several overarching barriers that must be addressed to facilitate the growth of the U.S. bioindustrial economy.These barriers include a fragmented and redundant regulatory landscape, deeply entrenched policies and incentives that still benefit the petrochemical incumbent, as well as significant workforce shortages.To successfully transition and establish itself as a global leader in the bioeconomy, the U.S. requires a comprehensive, government-wide strategy aimed at the radical transformation and restructuring of its industrial complex.
In 1986, the Environmental Protection Agency (EPA), the Food and Drug Adminis tration (FDA), and the U.S. Department of Agriculture (USDA) jointly published the U.S. Coordinated Framework for Biotechnology Products, which was updated in 2017 (7).This framework offers guidance and regulations for biotechnology products but does not address the increasing complexity of emerging bioproducts that often do not operate within a single agency's jurisdiction.This lack of clarity often results in companies having to file regulatory documents with multiple agencies, using different data and formats, leading to inefficiencies for both regulators and product developers.Stakeholders interviewed in this study suggest streamlining regulatory processes to enhance competitiveness against the fossil fuel-based incumbent, which historically received substantial policy and financial support (8).Some proposed an expedited regulatory pathway, based on robust risk assessments, to facilitate market entry for bio-based products which are inherently more sustainable.Others proposed a sciencebased approach to streamlining safety regulations, reducing redundancy in safety testing like animal testing of established chemicals, and suggested exploring chemical equivalent reach-across programs to boost competitiveness and expedite market entry for biomanufacturing products.The President's Council of Advisors on Science and Technology provided complementary recommendations in their report to the president.Specifically suggesting that regulatory agencies should draft updated and streamlined model pathways for review of emergent bioproducts, as well as establishing and training an inter-agency rapid response team to vet new crosscutting bioproducts (5).There may also be an opportunity for regulatory authorities to harness the potential of AI and advanced data analytics to streamline regulatory processes, bolstering efficiency, and reducing bottlenecks.As other nations expedite their regulatory review and approval procedures, it is now more critical than ever for the United States to address its regulatory bottlenecks to maintain its competitiveness and leadership role.
Industry leaders interviewed in this study all agreed industrial biorevolution had the potential to create millions of high-paying jobs across the country, including in economically and socially marginalized communities.A strong, well-trained, and diverse workforce is also necessary to manifest the bold promises outlined in the presidential EO and will require federal and state governments to offer incentives that facilitate collaboration between various educational institutions, including community colleges, historically Black colleges and universities, tribal colleges and universities, traditional 4-year universities, as well as K-12 schools.Such programs would help develop robust curricula and certification programs in biomanufacturing science and would ultimately help foster diversity by equipping individuals with the in-demand skills needed for immediate employment in the biomanufacturing industry.In rural areas and regions rich in sustainable biomass resources, fostering the development of biotechnology capabilities through investments in training programs and local infrastructure not only has the potential to create new employment opportunities for these communities but also to fuel the expansion of the U.S. bioeconomy (9).This critical need was also underlined in NASEM's Safeguarding the Bioeconomy report (1).
It is clear that biomanufacturing will have significant impacts on carbon emissions, economic opportunities, as well as national security.Promoting and integrating the ethical principle in the biotech industry has long been an area of U.S. policy develop ment.However, this study marks a seminal shift by incorporating the viewpoints of biotechnology practitioners into these policy discussions and by broadening their scope through the inclusion of nontraditional bioethics issues like sustainability.While various models have been examined to integrate social and ethical expertise into technology development, the valuable insights from this study are poised to help reshape future U.S. government policymaking.More importantly, this study underscores that for the U.S. to become the global leader in establishing standards and norms, it must first address the obstacles hindering the full realization and growth of its bioindustrial sector.

Limitations
While this study employed a robust methodology, certain limitations must be acknowl edged.The inclusion of a diverse range of BioMADE members was a strength, but not all members could be interviewed.Despite conducting interviews with strict not-forattribution policies and confidentiality measures, concerns around competitiveness may have influenced overall participation.It is also important to note that the state ments and recommendations provided by interviewees may not necessarily align with their organization's official stance, and that no broader inferences should be drawn beyond this particular sample.Finally, while all governments investing in the growth of bioindustrial manufacturing should also prioritize the integration of the 4S principles, it should be noted that the discussions by the interviewees mainly targeted U.S.-centric initiatives.

Conclusion
With rapid developments in biotechnology and biomanufacturing, there is a pressing need to create fresh frameworks for incorporating BioMADE's 4S principles into the development of these new technologies.Moreover, a narrow window exists for the U.S. to help promote impactful new norms as the field continues to expand globally, ultimately enhancing public acceptance and the success of industrial biotechnology.The insights, concerns, and recommendations detailed in this study are poised to inform future USG policymaking and norm-setting, shedding light on the crucial perspectives of industry practitioners.

TABLE 1
4S definitions a

TABLE 2
Participant list

TABLE 3 Main findings Perception Barriers Recommendations Key quotes
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TABLE 3
Main findings (Continued) What do the systems do when put together?And is the outcome something that would be weaponiza ble?" "I think right now there's kind of a chicken and egg problem.If the US government tomor row said we're only going to spend our dol lars with responsible companies.But who are the responsible companies?You can make an argument that it's the IGC companies, but like that's one level of a surety, but it's not a third-party level of a surety.It's really not anywhere near the equivalent of an ISO audit.What is the level of confidence that you would need to have before you're willing to redirect state, or Federal dollars to a limited set of economic actors?""Historically, the government had a responsibility to understand the safety and security implications of emerging technologies.I just don't see that kind of like large scale investment going into the National Lab architecture for bio." "We just have no ability to model or predict negative outcomes on any biological level.It seems like we should be working on that, since we're working furiously on the ability to design totally de novo biological functions." "Because biotech is so fragmented, safety and security can mean different things to different people, and the significance of it can be different." "If you're sponsored by the Department of Defense, you think about safety and security because you're forced to.If you are interested in more entrepre neurial work, you start to think about security from the perspective of intellectual property." "There are things/risks that you don't know you don't know." Risks associated with AI enabled synthesis of de novo molecules process using current tools less effective, if not somewhat blind.Lack of national-level regulation for non-U.S.based synthesis company Lack of regulation for U.S. companies that buy DNA from outside of the USA No existing capacity or expertise to properly assess how different biological functions would interreact with each other in a single cellular system and identify potential risks Lack of metrics or measurement techniques to assess whether organizations are successful at achieving set security goals Develop foreign staff consideration guidelines or requirements Explore export control policies Directly invest in research on the safety and security implications of new tech, and build risk models.Develop broadly available tools that estimate the risk and screen sequences Require all U.S. companies to purchase DNA from the verify provider Hold/fund workshops with cross-sector representa tion to try to develop potential policy recommen dations for the government to address the risks surrounding AI-derived proteins Invest in the development and rollout of genetically built-in IP protection with the ability to thwart an unauthorized user from being able to take advantage of an organism Policy research and development related to economic security in the context of the transition to a bio-based economy (e.g., policy surrounding who buys corn futures in the USA), including research on the data infrastructure needed for geo-economic forecasting.Invest/support supply chain visibility-understand where your feedstock is coming from and what the economic and security implications of that/assess geopolitical risk of sourcing-learn from other industries how to better understand your supply chain "Sustainability (Continued on next page)